ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2183G>A (p.Arg728Lys)

gnomAD frequency: 0.00001  dbSNP: rs80357335
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129301 SCV000184062 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-13 criteria provided, single submitter clinical testing The p.R728K variant (also known as c.2183G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2183. The arginine at codon 728 is replaced by lysine, an amino acid with highly similar properties. In one study, this variant was classified as likely to be neutral or of little clinical significance based on sequence alignment and chemical properties of the variant amino acid (Abkevich V et al. J. Med. Genet. 2004;41(7):492-507). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000658781 SCV000293348 uncertain significance not provided 2015-10-31 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2183G>A at the cDNA level, p.Arg728Lys (R728K) at the protein level, and results in the change of an Arginine to a Lysine (AGA>AAA). Using alternate nomenclature, this variant would be defined as BRCA1 2302G>A. This variant has been predicted likely neutral based on interspecific sequence variation (Abkevich 2004). BRCA1 Arg728Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Arg728Lys occurs at a position that is not conserved and is located in the DNA binding domain (Narod 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Arg728Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000129301 SCV000683017 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-27 criteria provided, single submitter clinical testing This missense variant replaces arginine with lysine at codon 728 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 2/60463 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000189). A multifactorial analysis also has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0331 and 0.1275, respectively (PMID: 31131967). This variant has been identified in 2/250524 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen RCV000658781 SCV000780576 uncertain significance not provided 2018-01-01 criteria provided, single submitter clinical testing
Counsyl RCV000077510 SCV000785012 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2017-03-15 criteria provided, single submitter clinical testing
Invitae RCV001340841 SCV001534673 likely benign Hereditary breast ovarian cancer syndrome 2023-12-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001800355 SCV002046288 uncertain significance not specified 2020-10-09 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000129301 SCV002538100 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-26 criteria provided, single submitter curation
University of Washington Department of Laboratory Medicine, University of Washington RCV000129301 SCV003847863 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Sharing Clinical Reports Project (SCRP) RCV000077510 SCV000109310 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2012-06-12 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077510 SCV000144323 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001354681 SCV001549357 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Arg728Lys variant identified in dbSNP (ID: rs80357335) as “With Uncertain significance allele”, ClinVar (as uncertain significance by Ambry Genetics, GeneDx, Color, Praxis, Counsyl, SCRP, and BIC), LOVD 3.0 (as "NA"), and UMD-LSDB (9x as uncertain significance). The variant was identified in control databases in 2 of 245450 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (Non-Finnish) population in 2 of 111322 chromosomes (freq: 0.000018), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The variant was reported in the literature as "likely to be neutral or of little clinical significance" by Abkevich (2004) and as "uncertain clinical significance” by Judkins (2005). The p.Arg728 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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